Method and apparatus for reduction of pain from electric shock therapies

ABSTRACT

A method and apparatus for pretreating a patient prior to a therapeutic painful stimulus, comprising the application of pain inhibiting stimuli to a patient prior to an application of the therapeutic painful stimulus. Applying pain inhibiting stimuli comprises the steps of sensing a need for the therapeutic painful stimulus, preparing to deliver the pain inhibiting stimuli to the patient prior to applying the therapeutic painful stimulus, and delivering the pain inhibiting stimuli to the patient prior to applying the therapeutic painful stimulus. The method and apparatus are embodied in modern, fully automatic, fully implantable, single or dual chamber atrial or ventricular cardioverter-defibrillators. The pain inhibiting prepulse method is intended primarily for use in conscious patients but may also be used in sleeping patients.

CROSS REFERENCE TO RELATED APPLICATIONS, IF ANY

This application is a continuation of application Ser. No. 09/152,382,filed Sep. 14, 1998, now U.S. Pat. No. 6,091,989.

This application claims the benefit under 35 U.S.C. §119(e) ofco-pending provisional application Serial No. 60/081,164, filed Apr. 8,1998, which is hereby incorporated by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

Not applicable.

REFERENCE TO A MICROFICHE APPENDIX

Not applicable.

BACKGROUND OF THE INVENTION

1. Field of the Invention.

This invention relates generally to therapeutic painful stimuli such aselectric shock pulses, and more particularly to the process of reducingthe pain associated with these therapeutic painful stimuli by modifyinga patient's pain perception and response using prepulse inhibition(PPI). Further, this invention relates to therapeutic electric shocksdelivered to patients by implantable cardioverter-defibrillators (ICDs)as treatment for atrial or ventricular arrhythmias. It relatesparticularly to reducing the pain associated with atrial defibrillationin a conscious patient.

2. Background Information.

Implantable cardioverter-defibrillators (ICDs) deliver high-voltageelectrical pulses (shocks) to terminate cardiac arrhythmias. Thistreatment is highly successful, but it is severely painful and may evenstun a patient temporarily. Initially, painful and startling therapeuticshocks were considered acceptable only as a treatment of last resort.Because of this, ICD therapy was restricted to ventricular arrhythmiaswhich were both life-threatening and refractory to all other therapies.Subsequently, however, ICDs have become first-line therapy for patientswith a history of life-threatening ventricular arrhythmias and patientsat risk for life-threatening ventricular arrhythmias. Controlled studieshave shown that ICDs are superior to alternative therapy for specificgroups of these patients. These studies are the Multicenter AutomaticDefibrillator Implantation Trial (Moss et al, N Engl J Med 1996; 335:1933-1940) and the Antiarrythmics Versus Implantable DefibrillatorsTrial (Zipes et al, N Engl J Med 1997; 337: 1576-1583).

As ICD therapy has been applied to larger numbers of patients withventricular arrhythmias, more attention has been paid to the painful andstartling nature of the therapeutic shocks and the psychologicalcomplications of this therapy. These factors limit patient acceptance ofICD treatment of arrhythmias in conscious patients. A significantfraction of patients report anxiety and fear of painful ICD shocks ((1)Dougherty, Psychological reactions and family adjustment in shock versusno shock groups after implantation of internal cardioverterdefibrillator, Heart Lung 1995; 24: 281-291—(2) Dunbar et al, Cognitivetherapy for ventricular dysrhythmia patients, J Cardiovasc Nursing 1997;12: 33-44—(3) Luderitz et al, Patient acceptance of ICD devices:Changing attitudes, Am Heart J 1994; 127: 1179-1184—(4) Morris et al,Psychiatric morbidity following implantation of the automatic ICD,Psychosomatics 1991; 32: 58-64). Shocks correlate with anxiety,psychiatric morbidity and psychological distress in ICD recipients. Inone study 87.5% of patients experienced “nervousness” after a shock and12.5% experienced “terror” or “fear.” Patients who have experiencedlarge numbers of repetitive shocks frequently suffer from a form ofpost-traumatic stress disorder.

Recently, ICD therapy has been applied to treatment of atrialarrhythmias, particularly atrial fibrillation ((1) Lau et al, Initialclinical experience with an implantable human atrial defibrillator, PACE1997; 20: 220-225—(2) Timmersman et al, Early clinical experience withthe Metrix automatic implantable atrial defibrillator, European Heart J1997; 134). Although atrial fibrillation usually is notlife-threatening, it is the most common arrhythmia requiringhospitalization in the United States. It causes potentially disablingsymptoms of palpitations, shortness of breath, or chest pain and is animportant cause of stroke.

The painful and startling nature of ICD shocks are considered aparticular limitation for patient acceptance of ICD treatment of atrialfibrillation. It has been stated in recent published literature (Cooperet al, Internal atrial defibrillation in humans: Improved efficacy ofbiphasic waveforms and the importance of phase duration, Circulation1997; 96: 2693-2700) that the ultimate acceptance of a fully automaticatrial defibrillator will depend on the reduction of pain to acceptablelevels.

To this end, present state-of-the-art holds that a primary method ofreducing the pain associated with these shocks is to reduce the strengthof the shock pulse as measured by energy or voltage. This methodrequires a significant decrease in the shock strength required todefibrillate with a success rate of 50%. This shock strength is known asthe defibrillation threshold. Recent studies have focused on reducingthe atrial defibrillation threshold by altering the shape (waveform) ofthe delivered shock pulse or the locations of the electrodes (electrodeconfiguration) through which these shocks are applied. The fundamentalhypothesis is that lowering of the defibrillation threshold will permitatrial defibrillation with weaker shocks and thereby decrease the painassociated with these shocks in patients.

The shock strength judged tolerable for defibrillation in consciouspatients has differed in previous studies, but is generally in the rangeof 0.1-0.5 joules (J). Zipes (Zipes et al, Clinical transvenouscardioversion of recurrent life-threatening ventriculartachyarrhythmias: Low energy synchronized cardioversion of ventriculartachycardia and termination of ventricular fibrillation in patientsusing a catheter electrode, Am Heart J 1982; 103: 789-794) reported thatshocks of 0.5 J or less delivered between electrodes in the superiorvena cava and right ventricle were tolerable for treatment ofventricular tachycardia. However, using the same electrode system,Perelman (Perelman et al, Assessment of prototype implantablecardioverter for ventricular tachycardia, Br Heart J 1984; 52: 385-391)found that 3 of 9 patients reported severe discomfort at a shockstrength of 0.1 J. Nathan (Nathan et al, Internal transvenous low energycardioversion for the treatment of cardiac arrhythmias, Br Heart J 1984;52: 377) delivered transvenous shocks to 19 conscious patients forvarious atrial and ventricular arrhythmias. Fourteen of 19 patientsdescribed severe discomfort with shock strengths 0.5 J. Murgatroyd(Murgatroyd et al, Efficacy and tolerability of transvenous low energycardioversion of paroxysmal atrial fibrillation in humans, J Am CollCardiol 1995; 25: 1347-1353) determined the range of tolerable shockstrengths for the most favorable electrode configuration for atrialdefibrillation (right atrium to distal coronary sinus). Although therange of shock strengths tolerated without severe discomfort was 0.1 to1.2 J, seven of 19 patients found even 0.1 J shocks intolerable. Using adifferent electrode system, Steinhaus (Steinhaus et al, Atrialdefibrillation: are low energy shocks acceptable to patients? PACE 1996;19: 625) delivered shocks of 0.4 J and 2.0 J shocks in randomized order.Patients reported no difference in perceived pain between the two shockstrengths. Both shock strengths were given discomfort scores ofapproximately 7 on a scale of 0-10.

However, Steinhaus found that the second shock was judged significantlymore painful than the first shock, independent of shock strength. Thisobservation is important because a strategy for reducing pain indefibrillation of arrhythmias which are not life-threatening (such asatrial fibrillation) contemplates clinical use of defibrillation shockswith strength near the defibrillation threshold. The hypothesis is that,even if multiple shocks are required to terminate the arrhythmia,multiple weaker shocks will be better tolerated than one strong shock.Steinhaus' data suggest that any clinical benefit in pain reductionachieved by delivering clinical defibrillation shocks with strength nearthe defibrillation threshold is likely to be offset by the increaseddiscomfort associated with subsequent shocks as weak as 0.4 J.

Data reported for atrial defibrillation thresholds must be considered inthe perspective of these reported values for tolerable shock strengths.Cooper (Cooper et al, Internal cardioversion of atrial fibrillation insheep, Circulation 1993; 87: 1673-1686) measured the atrialdefibrillation threshold for multiple waveforms and electrodeconfigurations in sheep. They showed that a specific biphasic waveform(3 ms phase 1 and 3 ms phase 2) and a specific electrode configuration(right atrial appendage to distal coronary sinus) resulted in the lowestatrial defibrillation threshold for the combinations of electrodeconfigurations and waveforms tested (1.3±0.4 J). However, use of thiswaveform and electrode configuration in humans with paroxysmal(intermittent) atrial fibrillation, the principal treatment populationfor atrial ICDs, resulted in atrial defibrillation thresholdsapproximately twice as high as in sheep. Johnson (Johnson et al,Circulation 1993; I 592) reported a value of 2.5±1.4 J and Murgatroyd(Murgatroyd et al, J Am Coll Cardiol 1995; 25: 1347-1353) reported avalue of 2.2±1.0 J. Therefore, the prior art does not teach a methodsufficient for the reduction of a patient's perceived pain during atrialdefibrillation shocks.

More recently, Cooper (Cooper et al, Internal cardioversion of atrialfibrillation: Marked reduction in defibrillation threshold with dualcurrent pathways, Circulation 1997; 96: 2693-2700) showed thatsequential shocks delivered through two different sets of electrodessignificantly decreased atrial defibrillation thresholds in sheep. Thedefibrillation threshold for this complex method (0.36±0.13 J) wassignificantly lower than that of the best single-pathway method (1.3±0.3J). Since the average atrial defibrillation thresholds in sheep areapproximately half that of the average atrial defibrillation thresholdsfor patients with paroxysmal atrial fibrillation, it was estimated thatthis newly determined method would provide average atrial defibrillationthresholds of slightly less than 1 J in patients. Thus, despite theadditional complexity of the implant procedure and possible additionalshort and long-term morbidity associated with this new method, it is notlikely to permit atrial defibrillation shocks without severe discomfortin the majority of patients. Therefore, this prior art does not teach amethod sufficient for the significant reduction of a patient's perceivedpain during atrial defibrillation. This prior art moreover requires theincreased cost, surgical complexity, and risk associated with twoadditional electrodes.

The method and apparatus of U.S. Pat. No. 5,332,400 issued to Alfernessdiscloses an implantable atrial defibrillator that provides a warning toa patient prior to delivery of an atrial shock pulse to cardiovert ordefibrillate the patient's atrial arrhythmia. The atrial defibrillatorapplies a warning electrical shock to the patient's atria when theapparatus determines that the atria require cardioversion ordefibrillation. The warning shock has an energy level lower than thatrequired to treat the arrhythmia but high enough to be discerned by thepatient without pain or other discomfort. The purpose of this warning isto provide sufficient time in advance of the therapeutic shock (in therange of 1 to 20 minutes) to afford a patient the opportunity to preparefor this painful and startling therapy. The Alferness method andapparatus demonstrate the limitation of the prior art to significantlyreduce the extreme pain perceived by a patient when the defibrillationtherapy is applied.

The method and apparatus of U.S. Pat. No. 5,439,481 issued to Adamsdiscloses an implantable atrial and ventricular defibrillator thatdiagnoses atrial and ventricular arrhythmias, automatically treats theventricular arrhythmias, but allows discretionary treatment of theatrial arrhythmias. Such discretionary control permits the patient toforego painful atrial defibrillation shocks based on a medicalassessment that the atrial arrhythmia is not significantly dysfunctionaland is amenable to less immediate and less urgent medical treatment. TheAdams method and apparatus further demonstrate the limitation of theprior art to alleviate the extreme pain perceived by a patient whenatrial defibrillation therapy is applied.

The method and apparatus of U.S. Pat. No. 5,630,834 issued to Bardydiscloses an implantable atrial defibrillator that determines whether apatient is asleep prior to delivery of an atrial shock pulse.Defibrillation shocks that would be extremely painful to a consciouspatient are delivered only when a patient is asleep. Bardy states thatalthough numerous patents and applications attempt to optimize shockwaveforms and electrode systems to reduce defibrillation thresholds (andtherefore pain), the reliable accomplishment of low thresholds for allpatients will remain a difficult and perhaps infeasible objective. Thismethod may require a patient to remain in atrial fibrillation for manyhours until the patient falls asleep. Thus it is not practical for somepatients who become symptomatic shortly after the onset of atrialfibrillation or for patients with ventricular arrhythmias who typicallyrequire treatment as soon as possible after the onset of the arrhythmia.Further, some patients have reported being awakened from sleep bypainful and startling ICD shocks. Thus, administration of shocks duringsleep is painful in some patients. In addition, a patient's knowledgethat he/she may be shocked while asleep may result in anticipatoryanxiety that interferes with sleep. The Bardy method and apparatusfurther demonstrate the limitation of the prior art to significantlyreduce the extreme pain perceived by a conscious patient whendefibrillation therapy is applied.

We therefore describe a method and apparatus to significantly diminishor eliminate the perceived pain by reducing the perceived intensity ofdefibrillation shocks and by inhibiting the startle response associatedwith these shocks. The clinical basis for the present invention is thefundamental physiologic principal of PPI. As will be appreciated from areview of the background discussion and the detailed description of thepreferred embodiments, the present invention overcomes the limitationsand shortcomings of the prior art.

In the field of neurophysiologic and neuropsychiatric research, it hasbeen long appreciated that the experienced intensity of a strong, abruptstimulus, and the behavioral (startle) response to this stimulus can bediminished by delivering a weak stimulus 30-500 ms prior to the strongstimulus ((1) Cohen et al, Sensory magnitude estimation in the contextof reflex modification, J Exper Psychology 1981; 7: 1363-1370—(2)Swerdlow et al, “Neurophysiology and neuropharmacology of short leadinterval startle modification,” Chapter 6 of Startle Modification:Implications for Neuroscience, Cognitive Science, and Clinical Science,Dawson et al, Cambridge Univ Press, 1997). This physiologic suppressionof the startle reflex is referred to as prepulse inhibition (PPI). PPIdecreases both the motor (startle) response and the subject's perceptionof the intensity of the startling stimulus (pain). Normal human subjectsconsistently rate startling stimuli as significantly less intense ifthese stimuli are preceded by an appropriate weak prestimulus than ifthey were presented alone.

The neural circuitry responsible for the sensorimotor modulation of PPIhas been studied extensively. These studies indicate that PPI reflectsthe activation of ubiquitous, “hard-wired,” behavioral gating processesthat are regulated by forebrain neural circuitry. PPI occurs invirtually all mammals, and can be elicited in humans and humans andexperimental animals using near-identical stimuli to produce strikinglysimilar response patterns (Swerdlow et al, Assessing the validity of ananimal model of deficient sensorimotor gating in schizophrenic patients,Arch Gen Psychiatry 1994; 51: 139-154). The importance of these findingsis that optimal stimulus parameters for PPI, and the neural substratesthat regulate PPI, can be studied easily in animal models. Thiscapability facilitates the application of PPI principles as disclosed inthe preferred embodiments of the present invention.

In one preferred embodiment of the present invention, a single,low-voltage, short-duration pulse (the prepulse) precedes a high-voltageshock pulse. The time interval between the prepulse and the shock pulseis set between 30 to 500 ms. The specific time interval is determined bya testing method which identifies the optimal interval for PPI. Theprepulse and therapeutic shocks may have arbitrary waveforms which arenot necessarily identical. For example, these may include monophasic orbiphasic capacitive-discharge pulses of the type presently used in ICDs,or a pulse waveform constructed specifically to reduce pain, such as arounded, slow-rise time, or ascending ramp waveform (Mouchawar et al,Sural nerve sensory thresholds of defibrillation waveforms, J Amer CollCard 1998: 31 (Suppl A): 373). At the time of implant of an atrial,ventricular, or dual-chamber ICD with the present invention incorporatedtherein, a physician first determines an appropriate electrode systemfor a given patient and the appropriate cardioversion or defibrillationenergy setting for that patient and electrode system. The physician thenadjusts the amplitude of the prepulse and intervening time intervalbetween the prepulse and the therapeutic shock pulse so as tosignificantly reduce or eliminate the patient's perceived pain andstartle response caused by the shock pulse. Typically, the shockstrength required for cardioversion or defibrillation is determinedwhile the patient is under the influence of a short-acting anesthetic.The prepulse amplitude and time interval are adjusted in the consciouspatient after the effects of any short-acting anesthetic has dissipated.Alternatively, the prepulse amplitude and time interval are adjusted ata postoperative programming study.

It is important to note that defibrillation shocks are associated with aprominent startle responses in many patients. Studies of other types ofstartle responses demonstrate that startle responses are actuallyincreased when warning stimuli preceded the startling stimuli atintervals (>1 sec) that are adequate to evoke conscious anticipation ofthe startling stimulus (prepulse facilitation). Thus a “warning”prestimulus which is sufficiently early to evoke a conscious responseprior to an ICD shock is likely to increase the shock-induced startleeffect. ICD recipients report severe discomfort related specifically tothe startling effects of defibrillating shocks. A long-delay “warning”prestimulus is a programmable option in some ICDs. This feature israrely activated because patients experience anxiety during theanticipatory interval following the “warning” prestimulus. The presentinvention overcomes these problems by suppressing the painful “jolt”associated with the defibrillation-induced startle reflex, usingautomatic, preconscious mechanisms evoked during a time interval (30-500ms) which is too short to stimulate anticipatory anxiety.

The methods and devices of the prior art that most nearly approach thenovel features of the present invention, which uses PPI to reduce theperceived pain of therapeutic electrical stimuli delivered to aconscious patient, are, in fact, quite remote from it. Their marginalrelevance can best be appreciated by a short, comparative description.

The method and apparatus of U.S. Pat. Nos. 5,314,448 and 5,366,485issued to Kroll and Adams disclose electrical pretreatment to aventricular fibrillating heart to permit the applied shock pulse todefibrillate the ventricles with less energy than may otherwise berequired. Pretreatment pulses and the treatment shock are deliveredthrough the same electrodes. The underlying hypothesis asserts thatelectrical pretreatment of a fibrillating heart is expected to achievetemporal organization of the ventricular cardiac cells, therebydiminishing the demands imposed on the defibrillation threshold for thedefibrillating shock pulse. As will become apparent in the descriptionof the preferred embodiments, the present invention differssignificantly from this prior art. The concept of electricalpretreatment of a fibrillating heart to assist the defibrillating shockpulse by reducing its level of required energy through temporal cardiacorganization is completely absent from the present invention.

The method and apparatus of U.S. Pat. No. 5,425,749 issued to Adamsdiscloses the delivery of an electrical preemptive cardioversion shockto a patient determined to have a life-threatening arrhythmia such asventricular fibrillation. The underlying hypothesis asserts that theshock strength required for defibrillation is directly related to theduration of fibrillation and that an electrical preemptive shockdelivered as soon as possible following the onset of an arrhythmia willreduce the total energy requirements for cardioversion ordefibrillation. The preemptive shock is thus delivered several secondsbefore the main cardioverting or defibrillating pulse. As will becomeapparent in the description of the preferred embodiments, the presentinvention differs significantly from this prior art. The concept ofelectrical preemptive cardioversion or defibrillation to quickly treat apatient and thereby to significantly reduce the size and energyrequirements of a defibrillator is completely absent from the presentinvention.

Despite the need in the art for an ICD apparatus or methods whichovercome the shortcomings and limitations of the prior art, none insofaras is known has been developed or proposed. Accordingly, it is an objectof the present invention to provide an implantable atrial, ventricular,or dual-chamber ICD method and apparatus that applies the clinicalscience related to sensorimotor gating to reduce or eliminate theperceived intensity of, and startle response to, the ICD's shock pulse.The present invention reduces or eliminates the pain by delivering atimed prepulse that reduces the perceived intensity of the shock pulse,and inhibits the startle response to the shock pulse. There are no suchteachings in the prior art.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a method and apparatus to pretreat apatient prior to a therapeutic painful stimulus, comprising the step ofapplying at least one pain inhibiting stimulus to a first part of apatient's body prior to an application of the therapeutic painfulstimulus to the same part or a second part of a patient's body. Thismethod is intended primarily for use in conscious patients, but it mayalso be used in sleeping patients.

The benefits of this invention will become clear and will be bestappreciated with reference to the detailed description of the preferredembodiments. Other objects, advantages and novel features will beapparent from the description when read in conjunction with the appendedclaims and attached drawings.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

FIG. 1 illustrates a single, startling pulse, an associated measurementof perceived pain and startle reflex magnitude, a prepulse preceding thesingle, startling pulse by a 30-500 ms interval, and an associated,significant reduction of the perceived pain and startle responseexhibited by a patient.

FIG. 2 illustrates a single, startling pulse, an associated measurementof perceived pain and startle reflex magnitude, a prepulse preceding thesingle, startling pulse by a 0.1-20 ms interval, and an associated,significant accentuation of the perceived pain and startle responseexhibited by a patient.

FIG. 3 illustrates an empirically determined relationship of prepulseintensity to the percentage of PPI.

FIG. 4A illustrates an active housing ventricular ICD implantedpectorally and attached to transvenous electrodes placed into thesuperior vena cava, coronary sinus, and right ventricle of a patient'sheart, and further attached to tip to ring pacing and sensing electrodesplaced into the right ventricle of a patient's heart.

FIG. 4B illustrates an active housing atrial or dual chamber implantedpectorally and attached to transvenous electrodes placed into thesuperior vena cava, right ventricle and coronary sinus of a patient'sheart, and further attached to bipolar pacing and sensing electrodesplaced into the right atrium and right ventricle of a patient's heart.

FIG. 5 illustrates the invention's primary defibrillation systemcomponents (analyzer—programmer, telemetry head, implantablecardioverter—defibrillator, and electrode system) and theirinterconnection for operation to implant and monitor an atrial orventricular ICD.

FIG. 6 illustrates the invention's primary ICD hardware and softwareelements and their interconnection for operation to diagnose atrial orventricular fibrillation and to deliver reduced-pain defibrillationtherapy using the principle of PPI.

FIG. 7 illustrates first a monophasic atrial or ventriculardefibrillation pulse, second a high amplitude, pain inhibiting,monophasic prepulse preceding the monophasic atrial or ventriculardefibrillation pulse, and third a high amplitude, pain inhibiting,biphasic prepulse preceding the monophasic atrial or ventriculardefibrillation pulse.

FIG. 8 illustrates first a biphasic atrial or ventricular defibrillationpulse, second a high amplitude, pain inhibiting, monophasic prepulsepreceding the biphasic atrial or ventricular defibrillation pulse, andthird a high amplitude, pain inhibiting, biphasic prepulse preceding thebiphasic atrial or ventricular defibrillation pulse.

FIG. 9A illustrates control, charge, and discharge circuitry forcharging and delivering a monophasic atrial or ventriculardefibrillation pulse or a high amplitude, inhibiting prepulse. Thecircuitry illustrates charging and discharging each pulse from the samecircuitry.

FIG. 9B illustrates control, charge, and discharge circuitry forcharging and delivering a monophasic or biphasic atrial or ventriculardefibrillation pulse or a high amplitude, inhibiting, monophasic orbiphasic prepulse. The circuitry illustrates charging and dischargingeach pulse from the same circuitry.

FIG. 10 illustrates first a monophasic atrial or ventriculardefibrillation pulse, second a low amplitude, pain inhibiting,monophasic prepulse preceding the monophasic atrial or ventriculardefibrillation pulse, and third a low amplitude, pain inhibiting,biphasic prepulse preceding the monophasic atrial or ventriculardefibrillation pulse.

FIG. 11 illustrates first a biphasic atrial or ventriculardefibrillation pulse, second a low amplitude, pain inhibiting,monophasic prepulse preceding the biphasic atrial or ventriculardefibrillation pulse, and third a low amplitude, pain inhibiting,biphasic prepulse preceding the biphasic atrial or ventriculardefibrillation pulse.

FIG. 12 illustrates control, charge, and discharge circuitry forcharging and delivering a monophasic or biphasic atrial or ventriculardefibrillation pulse or a low amplitude, inhibiting, monophasic orbiphasic prepulse. The circuitry illustrates charging and dischargingeach pulse from separate circuitry.

DETAILED DESCRIPTION Clinical Background and Theory of Operation

Startle response is a well-understood simple behavior that has beenstudied systematically in the field of neurobiology. The systematicstudy has drawn on the characteristics of startle as a quantifiable,parametrically sensitive behavior of animals and humans. The startleresponse is regulated by forebrain circuitry and appears to exhibitstriking similarities across species. The startle response demonstratesimportant forms of plasticity, including habituation andfear-potentiation. One form of startle plasticity relates to itsamplitude modulation when the startle reflex is preceded by aprestimulus, or prepulse. The amplitude modulation is called PPI, whichis the normal suppression of the startle reflex when the intensestartling stimulus is preceded 30 to 500 ms by a relatively weakprestimulus. In PPI, a weak prestimulus inhibits a reflex response to apowerful sensory stimulus. Virtually all mammals and primates exhibitPPI. PPI reflects the activation of ubiquitous, “hard-wired,”sensorimotor gating processes that are regulated by forebrain neuralcircuitry.

Sensorimotor (startle response) modulation can also result in thepotentiation of the startle reflex. Startle magnitude is increased whenthe startling stimulus is preceded at very short (<20 ms) or longintervals (>1000 ms) by prestimuli. This modulation is called prepulsefacilitation, and is most evident with weak prestimuli. Prestimulusmodulation changes from facilitation to inhibition with increasingprepulse interval and intensity. Prepulse facilitation reappears as thetime intervals become extended. It is not known whether PPI and prepulsefacilitation are opposing forms of sensorimotor modulation that resultfrom activity within either a single brain system or two separablesubstrates.

The brain circuitry that mediates the inhibitory effect of theprestimulus does not deviate from the primary startle circuit by morethan 1 to 2 neurons, with an approximate 7.5 ms conduction time “out”from and 7.5 ms conduction time “back” to the primary startle circuit.The circuitry that mediates PPI is simple and is integrally related tothe primary startle circuit. The forebrain circuitry “sets the gain” forPPI, involving several different neurotransmitter systems that regulatethe amount of sensorimotor inhibition. Therefore, the regulation ofstartle facilitation is maximal with weak prestimuli at very short timeintervals and startle inhibition is maximal with more intense prestimuliat relatively “longer” short time intervals.

In addition to suppressing the motor component of the startle reflexresponse to intense, abrupt stimuli, prestimuli modify the perceivedintensity of these stimuli. Subjects rate the intensity of loud noisebursts as being lower when those bursts are preceded by prepulses,compared to noise bursts without prepulses (Perlstein et al, Leadstimulation effects on reflex blink, exogenous brain potentials, andloudness judgments, Psychophysiology 1993; 30: 347-358). Thus, prepulsesinhibit both the perceived intensity of, and the motoric response to,startling stimuli.

Most important to the present invention, the cardioversion ordefibrillation pulse delivered by an ICD result in subjective pain anddiscomfort perceived by a patient as well as an objective, physiologic,motoric, startle response by the patient. FIG. 1 and FIG. 2 illustratethe underlying neurobiologic principles in the attenuation oraccentuation of pain through startle response modulation using anelectrical prepulse.

FIG. 1 demonstrates the amplitude modulation of a patient's perceptionof or response to a painful stimulus due to PPI. The toptime-versus-voltage graph in FIG. 1 represents an intense, painfulstimulus 10 to a patient, such as a defibrillation shock pulse, and thepatient's perception of or response to that stimulus illustrated in thebar graph 12. Note that in FIG. 1 and subsequent FIG. 2, bar graph 12may represent a measure either of a patient's subjective perception ofthe painful stimulus 10or physiologic response to the painful stimulus10, such as startle. The measured value of the patient's perception ofor response to painful stimulus 10 is illustrated in the bar graph 12 asa “5” on a scale from 0 to 10, with 10 representing a measurement ofgreatest intensity. The bottom time-versus-voltage graph in FIG. 1represents an intense, painful stimulus 18 to a patient, such as adefibrillation shock pulse. Painful stimulus 18 is preceded by a weakerprepulse 14 and separated by a predetermined time interval 16. Thepatient's associated perception of or response to the combined effectsof painful stimulus 18 and prepulse 14 are illustrated in the bar graph20, which corresponds to the bar graph 12 in the top panel. The measuredvalue is illustrated in the bar graph 20 as a “1” on a scale from 0 to10. FIG. 1 thereby illustrates that the amplitude, duration, andpreceding time interval for the prepulse were predetermined to modulatethe patient's response in the form of PPI, thereby reducing a patient'spain, discomfort, or startle.

Similarly, FIG. 2 demonstrates the amplitude modulation of a patient'sperception of or response to a painful stimulus due to prepulsefacilitation. The top time-versus-voltage graph in FIG. 2 againrepresents an intense stimulus 10 to a patient, such as a defibrillationshock pulse, and the patient's subjective perception of or physiologicresponse to the painful stimulus 10, such as startle. The measured valueof the patient's perception of or response to painful stimulus 10 isillustrated in the bar graph 12 as a “5” on a scale from 0 to 10, with10 representing a measurement of greatest pain. The top graph in FIG. 2is identical in all respects to the top graph in FIG. 1. The bottomtime-versus-voltage graph in FIG. 2 represents an intense, painfulstimulus 26 to a patient, such as a defibrillation shock pulse, which ispreceded by a weaker prepulse 22. Prepulse 22 precedes intense stimulus26 by predetermined time interval 24. Note that predetermined timeinterval 24 is much shorter than predetermined time interval 16 of FIG.1. The patient's associated perception of or response to the combinedeffects of painful stimulus 26 and prepulse 22 are illustrated in thebar graph 23, which corresponds to the bar graph 12 in the top panel andbar graph 20 in the bottom panel of FIG. 1. This measured value isillustrated in the bar graph 28 as a “9” on a scale from 0 to 10. FIG. 2thereby illustrates that the amplitude, duration, and preceding timeinterval for the prepulse were predetermined to modulate the patient'sresponse in the form of prepulse facilitation, thereby accentuating apatient's pain, discomfort, or startle.

Although both the prepulse and startling pulse are shown in FIGS. 1 and2 as square waves for illustrative purposes, the pulses may havearbitrary waveform shape and varying amplitude and duration.

Many studies have been conducted to characterize PPI in humans. In atypical method for demonstrating the increase in PPI with increasedprepulse intensity (Swerdlow et al, Assessing the validity of an animalmodel of deficient sensorimotor gating in schizophrenic patients, ArchGen Psychiatry 1994; 51: 139-154), acoustic stimuli are deliveredthrough headphones with a continuous 70-dB(A) background white noise.Startle pulses (40 ms-duration bursts of 118-dB(A) white noise) ispresented alone or 100 ms following a 20 ms-duration prepulse burst ofwhite noise at 2, 4, 8, or 16 dB(A) above the background noise. Eachstartle pulse and prepulse combination is administered multiple times,in random order. PPI is defined as the percentage of reduction instartle amplitude in the presence of the prepulse compared with theamplitude in the absence of the prepulse. Thus, a high percentage scoreindicates a high degree of PPI. Analysis of variance (ANOVA) withrepeated measures on trial type can be used to reveal a significanteffect of prepulse intensity on PPI Additionally, a thresholdsensitivity for the reduction of startle amplitude can be identified.Using the stimulus parameters described above, this typically occurswith prepulse intensities approximately 4 dB above the background noise.

FIG. 3 clearly illustrates the important relationship 48 betweenprepulse intensity and the percentage of PPI for a constant prepulseinterval (time between prepulse and pulse). The reduction of startleamplitude increases with increasing prepulse intensity when prepulseinterval is held constant. The results from the illustrative, acoustictrial have been repeated for other intense stimuli (e.g. air puff, shockand light flash) and their associated perceived pain or physiologicresponse. The results are consistent with the illustrated relationshipand demonstrate a universal relationship of PPI to startle responseacross stimulus modalities. As importantly, it has been shown that PPIoccurs when the prestimulus and the startling stimulus are in the sameor different sensory modalities. One example would be an acousticallyderived prestimulus coupled with a startling stimulus that iselectrically derived. Another example would be a tactile derivedprestimulus coupled with a startling stimulus that is optically derived.

Preclinical studies suggest that certain medications can increase theamount of prepulse inhibition. For example, in some conditions, prepulseinhibition was enhanced by the atypical antipsychotic clozapine. Becauseincreased PPI may be associated with a reduction in the experience of,and response to a startling stimulus, it may be desirable, under certaincircumstances, to utilize specific medications to enhance theeffectiveness of PPI in reducing the perception of, and/or response to adefibrillation shock. Medication may be administered on an as-neededbasis to patients in advance of a period of planned defibrillation, oron an ongoing basis to patients who require intermittent defibrillation.

Description of the Principle Physical Elements

FIGS. 4A, 4B, 5 and 6 illustrate the principle physical elements of theinvention. The figures illustrate a fully implantable atrial orventricular cardioverter—defibrillator pulse generator (ICD) 30 thatembodies the present invention and shown in association with aschematically illustrated human heart 34 and 38. The portions of theheart illustrated in FIGS. 4A and 4B are the right atrium 34 (RA), theleft atrium (LA), the right ventricle 38 (RV), and the left ventricle(LV).

ICD pulse generator 30 generally includes a housing 46 for hermeticallysealing the internal circuits and programming 150 of ICD 30 to bedescribed hereinafter, a right atrial/superior vena cava endocardialhigh-voltage lead 40, a coronary sinus/great cardiac vein, endocardialhigh-voltage lead 42, a right ventricle endocardial high-voltage lead44, a right atrium pace/sense lead 50, and a right ventricle pace/senselead 52. Each of the leads comprise an insulative lead body. The housing46 of ICD 30 may be provided with some or all portions without plasticinsulation (for example parylene or silicone rubber). The uninsulatedportions of the housing 46 optionally serve as a prepulse ordefibrillation electrode, used to deliver a prepulse or a high-voltagedefibrillation shock pulse to the atria, ventricles or both atria andventricles. High-voltage leads 40, 42, and 44 further compriseelectrodes capable of conducting high voltage currents anddefibrillation coil electrodes. They may be fabricated from platinum,platinum alloy, or other materials known to be usable in ICD electrodes.Leads 40, 42, and 44 are used to deliver a prepulse or a high-voltagedefibrillation shock pulse to either the atria or ventricles. Lead 50further comprise a tip electrode and a ring electrode, and isconstructed to enable bipolar sensing of electrical activations of theright atrium 34. Lead 52 further comprise a tip electrode and a ringelectrode, and is constructed to enable bipolar sensing of electricalactivations of the right ventricle 38. Although they are shownseparately in FIG. 4 for clarity, one or more of the high-voltage leads40, 42, and 44 and one or more of the pace-sense leads 50 and 52 may becombined into a single multiconductor lead. The enclosure 46 and theendocardial leads 40, 42, 44, 50 and 52 are arranged for establishingelectrical contact with the heart and to be implanted beneath the skinof a patient and so as to render ICD 30 fully implantable.

Within the enclosure 46, ICD 30 includes electrode switching circuitry188. Leads 40, 42, 44, 50 and 52 are coupled to the electrode switchingcircuitry via connector block 48. Leads 50 and 52 are further coupledcommunicatively to pacer timing/control circuitry 174 and to electrogramsensing and conditioning circuitry 154. Lead 50 therefore forms acomplete pace/sensing lead system for pacing and sensing electricalactivations of the right atrium. Lead 52 therefore forms a completepace/sensing lead system for pacing and sensing electrical activationsof the right ventricle.

The primary external components of ICD 30 are illustrated in FIG. 5.These are contrasted with the implantable elements (ICD pulse generator30 and endocardial leads illustrated by right ventricle lead 44) whichare shown within the human thorax 47 in this Figure. Ananalyzer-programmer system 130 is comparatively remote from the patient.Analyzer-programmer system 130 is coupled to a telemetry relay 134 viacommunication means 132, thereby able to compute and transmitprogramming instructions and programmable parameters via telemetry relay134 to ICD 30, and able to receive programmed parameters, patient-sensedparameters, and recorded electrical activations in the form of atrial orventricular electrograms via telemetry relay 134 from ICD 30. Telemetryrelay 134 is employed near or on the patient's body to communicativelycouple analyzer-programmer system 130 with ICD 30 via telemetry signals136. The instructions and parameters are transmitted to ICD 30 andreceived from ICD 30 using telemetry signals 136 comprising infrared,visible, radio-frequency electromagnetic, or ultrasound radiation.Analyzer-programmer system 130 and telemetry relay 134 are wellappreciated by those skilled in the art. For purposes of the presentinvention, these invention provisions and their general operation maycorrespond to inventions known in the prior art as disclosed in U.S.Pat. No. 4,809,697 issued to Causey and U.S. Pat. No. 4,958,632 issuedto Duggan, both incorporated herein by reference in their entireties.

The internal circuits and programming 150 of ICD 30 are illustrated inFIG. 6, and generally include electrode switching circuitry 188,electrogram sensing and conditioning circuitry 154, pacer timing/controlcircuitry 174, sense amplification and digitizing circuitry 156,microprocessor 152, random access memory 176, tachyarrhythmia andfibrillation detection software 158, address/data bus 178, address/databus 184, pacing, cardioversion and defibrillation charging and deliverycontrol software 160, charging and delivery control circuitry 180,charging circuitry 164, capacitor systems 162, discharge circuitry 168.A battery 166 is electrically and communicatively coupled to theinternal circuits and programming 150 and provides a sufficient sourceof energy to meet all energy requirements for long-term operation of ICD30.

FIG. 7 illustrates a monophasic atrial or ventricular defibrillationpulse 70, a high amplitude, pain inhibiting, short duration, monophasicprepulse 72 preceding the monophasic atrial or ventriculardefibrillation pulse, and a high amplitude, short duration, paininhibiting, biphasic prepulse 76 preceding the monophasic atrial orventricular defibrillation pulse. The monophasic atrial or ventriculardefibrillation pulse 70 serves as the intense, painful stimulus 18 ofFIG. 1. The high amplitude, short duration, pain inhibiting, monophasicprepulse 72 or the high amplitude, short duration pain inhibiting,biphasic prepulse 76 serves as the weaker prepulse 14 of FIG. 1 and isseparated by a predetermined time interval 74. FIG. 8 illustrates abiphasic atrial or ventricular defibrillation pulse 78, a highamplitude, pain inhibiting, monophasic prepulse 72 preceding thebiphasic atrial or ventricular defibrillation pulse, and a highamplitude, pain inhibiting, biphasic prepulse 76 preceding the biphasicatrial or ventricular defibrillation pulse. In this illustration, thebiphasic atrial or ventricular defibrillation pulse 78 serves as theintense, painful stimulus 18 of FIG. 1. Note that in FIGS. 7 and 8 theweaker strength of the prepulses relative to the intense pulses isdetermined by pulse duration.

FIG. 10 illustrates a monophasic atrial or ventricular defibrillationpulse 70, a low amplitude, pain inhibiting, monophasic prepulse 98preceding the monophasic atrial or ventricular defibrillation pulse, anda low amplitude, pain inhibiting, biphasic prepulse 100 preceding themonophasic atrial or ventricular defibrillation pulse. The monophasicatrial or ventricular defibrillation pulse 70 serves as the intense,painful stimulus 18 of FIG. 1, the low amplitude, pain inhibiting,monophasic prepulse 98 or the low amplitude, pain inhibiting, biphasicprepulse 100 serves as the relatively weaker prepulse 14 of FIG. 1 andis separated by a predetermined time interval 74. FIG. 11 illustrates abiphasic atrial or ventricular defibrillation pulse 78, a low amplitude,pain inhibiting, monophasic prepulse 98 preceding the biphasic atrial orventricular defibrillation pulse, and a low amplitude, pain inhibiting,biphasic prepulse 100 preceding the biphasic atrial or ventriculardefibrillation pulse. In this illustration, the biphasic atrial orventricular defibrillation pulse 78 serves as the intense, painfulstimulus 18 of FIG. 1. Note that in FIGS. 10 and 11 the weaker strengthof the prepulses relative to the intense pulses is determined by pulseamplitude. This contrasts with FIGS. 7 and 8 in which the weakerstrength of the prepulses relative to the intense pulses is determinedby pulse duration.

FIG. 9 A illustrates hardware and software elements that implement thedelivery of a monophasic atrial or ventricular prepulse fromhigh-voltage defibrillation circuitry primarily designed for monophasicatrial or ventricular defibrillation waveforms. FIG. 9A illustratescharge circuitry 82, capacitor system 84, discharge control circuitry80, monophasic discharge control lines 86, and monophasic dischargeswitching circuitry 88 for solid-state switching control of charging anddelivering a monophasic atrial or ventricular defibrillation pulse or ahigh amplitude, inhibiting prepulse. Charging and delivery controller160 of ICD 30 is coupled communicatively to the circuitry viaaddress/data bus 184 (which may be separate from address/data bus 178).The charging portion of controller 160 operates charging circuitry 82via control lines 182. Charge circuitry 82 charges capacitor system 84to predetermined energy and voltage levels prior to discharge. Thedelivery portion of controller 160 first utilizes discharge controlcircuitry 80 and operates switching circuitry 88 via control lines 86 tooutput a monophasic, truncated exponential prepulse 72, second operatesan internal timer for a predetermined amount of time to implementpredetermined time interval 74, and third operates switching circuitry88 to output a monophasic, truncated exponential cardioversion ordefibrillation shock pulse 70. The circuitry illustrates charging anddischarging a prepulse and a cardioversion or defibrillation pulse fromthe same circuitry. Prepulse 72 and 76 have leading-edge voltagesequivalent to leading-edge voltages for cardioversion or defibrillationshock pulse 70. Discharge control circuitry 80 modulates the prepulsewaveform duration and modulates the predetermined time interval 74.

FIG. 9B illustrates hardware and software elements that implement thedelivery of a monophasic or biphasic atrial or ventricular prepulse fromhigh-voltage defibrillation circuitry primarily designed for biphasicatrial or ventricular defibrillation waveforms. FIG. 9B illustratescharge circuitry 82, capacitor system 84, discharge control circuitry80, monophasic or biphasic discharge control lines 90 and 92, andmonophasic or biphasic discharge switching circuitry 94 and 96 forsolid-state switching control of charging and delivering a monophasic orbiphasic atrial or ventricular defibrillation pulse or a high amplitude,inhibiting, monophasic or biphasic prepulse. Charging and deliverycontroller 160 of ICD 30 is coupled communicatively to the circuitry viaaddress/data bus 184 (which may be separate from address/data bus 178).The charging portion of controller 160 operates charging circuitry 82via control lines 182. The charge circuitry 82 charges capacitor system84 to predetermined energy and voltage levels prior to discharge. Thedelivery portion of controller 160 first utilizes discharge controlcircuitry 80 and operates switching circuitry 94 and 96 via controllines 90 and 92 to output a monophasic 72 or biphasic 76 truncatedexponential prepulse, second operates an internal timer for apredetermined amount of time to implement predetermined time interval74, and third operates switching circuitry 94 and 96 to output amonophasic 70 or biphasic 78 truncated exponential cardioversion ordefibrillation shock pulse. FIG. 9B illustrates charging and dischargingcircuitry that implements biphasic waveforms using an H-bridge design.FIG. 9B further illustrates charging and discharging circuitry thatoutput a prepulse and a cardioversion or defibrillation pulse from thesame delivery circuits. Prepulse 72 and 76 have leading-edge voltagesequivalent to leading-edge voltages for cardioversion or defibrillationshock pulse 70 and 78. Discharge control circuitry 80 modulates theprepulse waveform duration and modulates the predetermined time interval74.

Capacitor system 84 illustrated in FIGS. 9A and 9B represents aconventional capacitor system for ICD 30. Capacitor system 84 isimplemented with one or more electrically coupled capacitors of up to1000 microfarads (μF) each. The electrical coupling circuitry implementseffective capacitance values for ICD 30 in the range of 10 to 250microfarads (μF), preferably in the range 60 to 120 μF. Capacitor system84 stores 0 to 40 joules (J) of energy, preferably 2 to 20 J forventricular defibrillation and 0.05 to 15 J for atrial defibrillation,and may be charged to 1000 V for the leading-edge voltage of prepulses72, 76 and defibrillation shock pulses 70, 78.

FIG. 12 illustrates hardware and software elements that implement thedelivery of a monophasic or biphasic prepulse from low-voltage,low-energy circuitry substantially different from high-voltagedefibrillation circuitry that implement the delivery of high-voltage,high-energy monophasic or biphasic defibrillation waveforms. FIG. 12illustrates charge and capacitor circuitry 104, discharge controlcircuitry 102, discharge control lines 108 and 110, and dischargeswitching circuitry 116 and 118 for a low amplitude, low-energy,monophasic or biphasic atrial or ventricular prepulse. FIG. 12 furtherillustrates charge and capacitor circuitry 106, discharge controlcircuitry 102, discharge control lines 112 and 114, and dischargeswitching circuitry 120 and 122 for a monophasic or biphasic atrial orventricular defibrillation pulse. Charging and delivery controller 160of ICD 30 is coupled communicatively to the circuitry via address/databus 184 (which may be separate from address/data bus 178). The chargingportion of controller 160 operates charging circuitry 104 and 106 viacontrol lines 182. The charge circuitry 104 charges its capacitor systemto a predetermined energy and voltage level for a low-voltage,low-energy prepulse. The charge circuitry 106 charges its capacitorsystem to a predetermined energy and voltage level for a high-voltage,high-energy cardioversion or defibrillation shock pulse. The deliveryportion of controller 160 first utilizes discharge control circuitry 102and operates switching circuitry 116 and 118 via control lines 108 and110 to output a monophasic 98 or biphasic 100 truncated exponentialprepulse, second operates an internal timer for a predetermined amountof time to implement predetermined time interval 74, and third utilizesdischarge control circuitry 102 and operates switching circuitry 120 and122 via control lines 112 and 114 to output a monophasic 70 or biphasic78 truncated exponential cardioversion or defibrillation shock pulse.The circuitry illustrates charging and discharging each pulse fromseparate circuitry. Prepulse 98 and 100 are programmable to permit theability to have stored energies, delivered energies, leading-edgevoltages, and prepulse waveform shapes substantially different from thestored energies, delivered energies, and leading-edge voltages forcardioversion or defibrillation shock pulse 70 and 78. Discharge controlcircuitry 102 modulates the prepulse waveform phase durations andamplitudes, and modulates the predetermined time interval 74.

Capacitor systems 104 and 106 illustrated in FIG. 12 representconventional capacitor systems for ICD 30. Capacitor systems 104 and 106may each be implemented with one or more electrically coupled capacitorsof up to 1000 microfarads (μF) each. Electrical coupling circuitry foreach capacitor system implements effective capacitance values for ICD 30in the range of 10 to 250 microfarads (μF), preferably in the range 60to 120 μF. Capacitor systems 104 and 106 each store 0 to 40 joules (J)of energy, preferably 2 to 20 J for ventricular defibrillation and 0.05to 15 J for atrial defibrillation, and each system may be charged to1000 V for the leading-edge voltage of prepulses 98, 100 anddefibrillation shock pulses 70, 78. Independent capacitor systems 104and 106 provide for prepulse waveform design substantially similar orsubstantially different from cardioversion and defibrillation waveformdesigns, as illustrated in FIGS. 7, 8, 10 and 11. In a preferredembodiment, capacitor system 104 is designed with different capacitivevalues and energy capabilities from the capacitance and energycapabilities of capacitor system 106. Capacitor system 104 implementsthe prepulse therapy with different capacitor values, stored anddelivered energies, leading-edge voltages, and waveform shapes.Alternatively, capacitor system 104 implements a square waveform androunded waveform as a prepulse. Capacitor systems 104 may be implementedas a pacing circuit and provide pacing pulses for prepulses 98 and 100.

The remainder of the invention is dedicated to the provision of cardiacpacing, cardioversion, defibrillation therapies, and apparatusprogramming techniques. For purposes of the present invention, theseinvention provisions may correspond to inventions known in the priorart. An exemplary apparatus is disclosed of accomplishing pacing,cardioversion, defibrillation, and programming functions. The generaloperation of the apparatus may correspond to that apparatus disclosed inU.S. Pat. No. 5,549,642 issued to Min, incorporated herein by referencein its entirety. As cited earlier, the exemplary apparatus isillustrated by FIGS. 4A through 12.

As illustrated in FIG. 4A, sensing electrodes 52 are located on or inthe right ventricle 38 and are coupled to the R-wave detection sectionof the electrogram sensing and conditioning circuitry 154, whichpreferably takes the form of an automatic threshold controlled sensingcircuit providing an adjustable sensing threshold as a function of themeasured electrogram amplitude. As illustrated in FIG. 4B, sensingelectrodes 50 are located on or in the right atrium 34 and are coupledto the P-wave detection section of the electrogram sensing andconditioning circuitry 154, which preferably takes the form of anautomatic threshold controlled sensing circuit providing an adjustablesensing threshold as a function of the measured electrogramn amplitude.The general operation of the P-wave and R-wave sensing and conditioningcircuitry 154 may correspond to circuitry disclosed in U.S. Pat. No.5,117,824 issued to Keimel and U.S. Pat. No. 5,282,837 issued to Adams,incorporated herein by reference in their entireties. Electrodeswitching circuitry 188 is used to select which of the availableelectrodes are coupled to the electrogram sensing and conditioningcircuitry 154 for use in digital signal analysis. Selection ofelectrodes is controlled by microprocessor 152 using the data andaddress bus 178, which selections may be varied as desired. Signals fromthe selected electrodes are provided to the wide band (0.02-200 Hz)amplifier, multiplexer, and analog to digital converter circuitry 156for conversion to multi-bit digital signals and to the random accessmemory 176 under the control of the microprocessor 152 for storage.Microprocessor 152 may employ digital signal processing techniques tocharacterize the digitized signals stored in memory 176 to recognize andclassify the patient's heart rhythm. Microprocessor 152 may employ anyof the numerous signal processing methods known to the art.

The pacer timing/control circuitry 174 includes programmable digitalcounters which control the basic time intervals associated with DDD,VVI, DVI, VDD, AAI, DDI, and other modes of single and dual chamberpacing well known to the art. Circuitry also controls escape intervalsassociated with antitachyarrhythmia pacing in both the atrium and theventricle, employing any antitachyarrhythmia pacing therapies known tothe art.

Intervals defined by pacing circuitry 174 include atrial and ventricularpacing escape intervals, the refractory periods during which sensedP-waves and R-waves are ineffective to restart timing of the escapeintervals and the pulse widths of the pacing pulses. The durations ofthese intervals are determined by microprocessor 152, in response tostored data in memory 176 and are communicated to the pacing circuitry174 via address/data bus 178. Pacer circuitry 174 also determines theamplitude of the cardiac pacing pulses under the control of themicroprocessor 152.

During pacing, the escape interval counters within pacer timing/controlcircuitry 174 are reset upon sensing of R-waves and P-waves as indicatedby signals on address/data bus 178, in accordance with the selected modeof pacing on time-out trigger generation of pacing pulses by paceroutput circuitry, which are coupled to electrodes 50 and 52. The escapeinterval counters are also reset on generation of pacing pulses, andthereby control the basic timing of cardiac pacing functions, includingtachyarrhythmia pacing. The durations of the intervals defined by theescape interval timers are determined by microprocessor 152, viaaddress/data bus 178. The value of the count present in the escapeinterval counters when reset by sensed R-waves and P-waves may be usedto measure the durations of R—R intervals, P—P intervals, P-R intervals,and R-P intervals, which measurements are stored in memory 176 and usedto detect the presence of tachyarrhythmias.

Microprocessor 152 operates as an interrupt driven device, and isresponsive to interrupts from pacer timing/control circuitry 174corresponding to the occurrence sensed P-waves and R-waves andcorresponding to the generation of cardiac pacing pulses. Theseinterrupts are provided via address/data bus 178. Any necessarymathematical calculations to be performed by microprocessor 152 and anyupdating of the values or intervals controlled by pacer timing/controlcircuitry 174 take place following such interrupts.

For example, in response to a sensed or paced ventricular depolarizationor R-wave, the intervals separating that R-wave from the immediatelypreceding R-wave, paced or sensed (R—R interval) and the intervalseparating the paced or sensed R-wave from the preceding atrialdepolarization, paced or sensed (P-R interval) may be stored. Similarly,in response to the occurrence of a sensed or paced atrial depolarization(P-wave), the intervals separating the sensed P-wave from theimmediately preceding paced of sensed atrial contraction (P—P interval)and the interval separating the sensed P-wave from the immediatelypreceding sensed or paced ventricular depolarization (R-P interval) maybe stored. Preferably, a portion of the memory 176 is configured as aplurality of recirculating buffers, capable of holding a precedingseries of measured intervals, which may be analyzed in response to theoccurrence of a pace or sense interrupt to determine whether thepatient's heart is presently exhibiting atrial or ventriculartachyarrhythmia.

The tachyarrhythmia and fibrillation detector 158 operates thealgorithms that process the arrhythmia signal data stored in memory 176.Detection of atrial or ventricular tachyarrhythmias, as employed in thepresent invention, may correspond to tachyarrhythmia detectionalgorithms known to the art. There are many algorithms known in the artfor processing arrhythmia data to determine if an atrial or ventriculartachyarrhythmia is present. For example, presence of atrial orventricular tachyarrhythmia may be confirmed by means of detection of asustained series of short R—R or P—P intervals. The average cyclelength, median cycle length, or cycle length of a certain percentage ofintervals (e.g. 75% or 100%) is less than the corresponding, programmedtachyarrhythmia detection interval and thus indicative of atachyarrhythmia. The suddenness of onset of the detected high rates ineach chamber, the interval stability of the high rate P—P and R—Rintervals the presence or absence of P-R association, informationrelated to the morphology of the electrograms corresponding to P and Rwaves in each chamber, or a number of other factors known to the art mayalso be measured at this time. Appropriate ventricular tachyarrhythmiadetection methodologies measuring such factors are described in U.S.Pat. No. 4,726,380 issued to Vollmann, U.S. Pat. No. 4,830,006 issued toHaluska, U.S. Pat. No. 4,880,005 issued to Pless, U.S. Pat. No.5,251,626 issued to Nickolls, and U.S. Pat. No. 5,545,186 issued toOlson, all incorporated herein by reference in their entireties. Anadditional set of tachycardia recognition methodologies is disclosed byOlson (Onset and stability for ventricular tachyarrhythmia detection inan implantable pacer-cardioverter-defibrillator, Computers inCardiology, Oct. 7-10, 1986, IEEE Computer Society Press, pages 167-170)also incorporated herein in its entirety. However, the advantages of thepresent invention is clearly practicable in conjunction with most priorart tachycardia detection algorithms. Atrial fibrillation detectionmethodologies in particular are disclosed in U.S. Pat. No. 5,205,283issued to Olson and U.S. Pat. No. 5,282,837 issued to Adams, in thepublication by Arzbaecher (Arzbaecher et al, Automatic tachycardiarecognition, PACE 1984; 541-547), and in the publication by Thakor(Thakor et al, Ventricular tachycardia and fibrillation detection by asequential hypothesis testing algorithm, IEEE Trans BiomedicalEngineering 1990; 37: 837-843), all of which are incorporated herein byreference in their entireties. Implementing such atrial and ventriculararrhythmia detection algorithms by a microprocessor is well within thepreview of one skilled in the art.

In the event that an atrial or ventricular tachyarrhythmia is detected,and an anti-tachyarrhythmia pacing regimen is desired, appropriatetiming intervals for controlling generation of anti-tachyarrhythmiapacing therapies are loaded from microprocessor 152 into the pacingtiming and control circuitry 174 to control the operation of the escapeinterval counters therein and to define refractory periods during whichdetection of P-waves and R-waves is ineffective to restart the escapeintervals.

Alternatively, circuitry for controlling the timing and generation ofantitachycardia pacing pulses as described in U.S. Pat. No. 4,577,633issued to Berkovits, U.S. Pat. No. 4,587,970 issued to Holley, U.S. Pat.No. 4,726,380 issued to Vollman, and U.S. Pat. No. 4,880,005 issued toPless, all of which are incorporated herein by reference in theirentireties, may also be used.

In the event that generation of a cardioversion or defibrillation pulseis required, microprocessor 152 employs an escape interval counter tocontrol timing of such cardioversion and defibrillation pulses, as wellas associated refractory periods. In response to the detection of atrialor ventricular fibrillation or tachyarrhythmia requiring a cardioversionpulse, microprocessor 152 activates the therapy charging and deliverycontroller 160 and the therapy charging and delivery control circuitry180, which initiates charging of the high voltage capacitor systems 162via the charging circuit 164 powered by the battery 166 and under thecontrol of high voltage charging control lines 182. The voltage on thehigh voltage capacitors is monitored, and in response to reaching apredetermined value set by microprocessor 152, results in generation ofa logic signal that terminates the charging of the capacitor systems162. Thereafter, timing of the delivery of the defibrillation orcardioversion pulse is controlled by the therapy charging and deliverycontroller 160 and the therapy charging and delivery control circuitry180. Following delivery of the fibrillation or tachycardia therapy themicroprocessor 152 then returns the device to cardiac pacing and awaitsthe next successive interrupt due to pacing or the occurrence of asensed atrial or ventricular depolarization. As described in precedingparagraphs, the control, charging, and delivery circuitry and logic forthe pain-suppressing prepulse therapies of the present invention areembodied within the structural framework of the modern implantablecardioverter—defibrillator as described herein.

One embodiment of an appropriate system for delivery and synchronizationof ventricular cardioversion and defibrillation pulses and forcontrolling the timing functions related to them is disclosed in moredetail in U.S. Pat. No. 5,188,105 issued to Keimel, incorporated hereinby reference in its entirety. Embodiments of appropriate systems fordelivery and synchronization of atrial cardioversion and defibrillationpulses and for controlling the timing functions related to them aredisclosed in more detail in U.S. Pat. No. 4,316,472 issued to Mirowskiand in U.S. Pat. No. 5,269,298 issued to Adams, both incorporated hereinby reference in their entireties. However, any known cardioversion ordefibrillation pulse control circuitry is believed usable in conjunctionwith the present invention. For example, circuitry controlling thetiming and generation of cardioversion and defibrillation pulses asdisclosed in U.S. Pat. No. 4,375,817 issued to Engle, in U.S. Pat. No.4,384,585 issued to Zipes, and in U.S. Pat. No. 4,949,719 issued toPless, all incorporated herein by reference in their entireties, mayalso be employed.

In the illustrated apparatus, delivery of the cardioversion ordefibrillation pulses is accomplished by the therapy discharge circuitry168, under control of circuitry 180 via control bus 186. Therapy controlcircuitry 180 determines whether a monophasic or biphasic pulse isdelivered, the polarity of the electrodes, and which electrodes areinvolved in delivery of the pulse. Therapy discharge circuitry 168includes high voltage switches which control which electrodes 40, 42,44, and 46 are coupled together during delivery of the pulse.Alternatively, electrodes intended to be coupled together during thepulse may simply be permanently coupled to one another, either exteriorto or interior of the device housing, and polarity may similarly bepre-set, as in current implantable defibrillators. An example of outputcircuitry for delivery of biphasic pulse regimens to multiple electrodesystems may be found in U.S. Pat. No. 4,727,877 issued to Kallok and inU.S. Pat. No. 4,953,551 issued to Mehra, both incorporated herein byreference in their entireties. An example of circuitry which may be usedto control delivery of monophasic pulses is set forth in U.S. Pat. No.5,163,427 issued to Keimel, incorporated herein by reference in itsentirety. However, output control circuitry as disclosed in thepreviously cited U.S. Pat. No. 4,953,551 issued to Mehra, or U.S. Pat.No. 4,800,883 issued to Winstrom, incorporated herein by reference inits entirety, may also be used in conjunction with a apparatus embodyingthe present invention for delivery of biphasic pulses.

In the event that both atrial and ventricular defibrillation areavailable, ventricular defibrillation may be accomplished using higherpulse energy levels than required for atrial defibrillation and mayemploy the same or a different electrode set as those electrodes usedfor atrial defibrillation. For example, electrodes 40 (rightatrial/superior vena cava) and 42 (coronary sinus/great vein) may beemployed for atrial defibrillation. Electrodes 40 and 44 (rightventricle) might be employed for ventricular defibrillation, withelectrode 40 coupled to electrode 46 (device housing). One particularlydesirable embodiment of the invention employs only the rightatrial/superior vena cava electrode 40, the coronary sinus/great cardiacvein electrode 42 and the right ventricular electrode 44. During atrialdefibrillation, electrodes 40 and 46 are coupled in common to oneanother, and the atrial defibrillation pulse is delivered between theseelectrodes and electrodes 42. During ventricular defibrillation,electrodes 40 and 46 are coupled in common with one another, and theventricular defibrillation pulse is delivered between these electrodesand electrode 44. This particular set of electrodes thus providesoptimized defibrillation pulse regimens for both atrial and ventriculardefibrillation, by simply switching the software or hardware controlledconnections of the coronary sinus/great vein electrode 42 and the rightventricle electrode 44. In another particularly desirable embodiment ofthe invention the same lead configuration is used for both atrial andventricular defibrillation. Electrodes 40 and 46 are coupled in commonwith one another, and the atrial or ventricular defibrillation pulse isdelivered between these electrodes and electrode 44. This particular setof electrodes avoids the need for a coronary sinus/great vein electrode42 and facilitates delivery of an atrial defibrillation shock with astrength that exceeds the ventricular upper limit of vulnerability.

Functional switching circuitry well known in the art may be employed inhigh voltage output circuit 168, such that the circuitry includes highvoltage switches individually controlled by signals on control bus 186.These switches allow connection of any of the described electrodes toeither the positive or the negative terminals of the capacitor systems162. As illustrated, any combination of electrodes may be selected, anypolarities desired may be provided, and monophasic or biphasic pulsesmay be delivered, depending upon control signals on control bus 184. Inthe event that a reduced set of available electrode configurations isdesired, the switching circuitry may be simplified. An example ofswitching circuitry may be found in the cited patent issued to Min (U.S.Pat. No. 5,549,642).

In modern ICDs, the particular therapies are programmed into the deviceat the time of implant or later by the physician, and a menu oftherapies is typically provided for such programming by theanalyzer-programmer system 130. For example, on initial detection of anatrial or ventricular tachycardia, an antitachycardia pacing therapy maybe selected and delivered to the chamber in which the tachycardia isdiagnosed or to both chambers. On redetection of tachycardia, a moreaggressive anti-tachycardia pacing therapy may be delivered. If repeatedattempts at anti-tachycardia pacing therapies fail, a higher voltagecardioversion pulse may be selected thereafter. Therapies fortachycardia termination may also vary with the rate of the detectedtachycardia, with the therapies increasing in aggressiveness as the rateof the detected tachycardia increases. For example, fewer attempts atanti-tachycardia pacing may be undertaken prior to delivery ofcardioversion pulses if the rate of the detected tachycardia is above apreset threshold. The cited references in conjunction with descriptionsof prior art tachycardia detection and treatment therapies areapplicable here as well. As described in preceding paragraphs, theprogramming logic and algorithms for the pain-suppressing prepulsetherapies of the present invention are embodied within the structuralframework for programming modern ICDs as described herein.

In the event that atrial or ventricular fibrillation is identified, thetypical therapy will be delivery of a high amplitude defibrillationpulse, typically 10 joules or more in the case of ventricularfibrillation and 10 joules or less in the case of atrial defibrillation.Lower energy levels will be employed for cardioversion. As in the caseof currently available implantable pacemakers and ICDs, and as discussedin the cited references, it is envisioned that the amplitude of thedefibrillation pulse may be incremented in response to failure of aninitial pulse to terminate fibrillation. Prior art patents illustratingsuch pre-set therapy menus of anti-tachycardia therapies include thepreviously cited U.S. Pat. No. 4,587,970 issued to Holley, U.S. Pat. No.4,726,380 issued to Vollmann, and U.S. Pat. No. 4,830,006 issued toHaluska.

While the invention that is disclosed is embodied in a dual chamberpacemaker and ICD, the invention may also be usefully practiced insubstantially simpler devices. For example, the illustrateddefibrillation electrodes may simply be coupled to an implantable atrialcardioverter as disclosed in U.S. Pat. No. 3,738,370 issued to Charmsand U.S. Pat. No. 5,282,837 issued to Adams, incorporated herein byreference in their entireties. Similarly, while the electrodes employedfor atria sensing and pacing are disclosed as mounted to the atriallead, these electrodes might alternatively take the form of ringelectrodes mounted to either the ventricular lead or the coronarysinus/great vein lead or on a separate electrode.

From the foregoing preferred embodiments, it can be seen that thepresent invention provides a new and improved fully implantable atrialdefibrillator and a new and improved fully implantablecardioverter—defibrillator, each of which is fully automatic and whichis safe in use.

Description of the Principle Methods

ICD pulse generator 30 is implanted in a pectoral or abdominal pocket.When an arrhythmia occurs, ICD 30 detects it and charges the outputcapacitors. ICD 30 also activates the circuits required to deliver theprepulse. After the output capacitors for the therapeutic pulse arecharged, ICD 30 may optionally confirm that the arrhythmia persists. Inatrial fibrillation, ICD 30 may also wait until the interval betweensensed QRS complexes exceeds a predetermined, programmable value tominimize the risk of inducing ventricular fibrillation by a shock in theventricle's vulnerable period. A typical minimum interval is 500 ms.

The prepulse is delivered synchronously with the sensed QRS complex. Theprepulse is synchronized to the local bipolar electrogram recorded fromthe right-ventricular sensing electrodes 52 or to a far-fieldelectrogram which uses the active housing 46 or right-ventriculardefibrillating electrode 44. ICD 30 may transmit a telemetry pulse atthe time of prepulse delivery. This telemetry pulse can be detected byanalyzer-programmer system 130 and telemetry relay 134 for ICD 30. Thetherapeutic shock is delivered 20-200 ms later. The preferred intervalbetween the prepulse and therapeutic pulse is the shortest intervalwhich optimizes PPI. Optimal PPI occurs at time intervals ofapproximately 100 ms, well within the ventricle's absolute refractoryperiod. A shortest, optimal prepulse interval eliminates the risk ofinducing ventricular fibrillation by a therapeutic shock deliveredduring atrial fibrillation or ventricular tachycardia. The strength oftherapeutic shocks can be less than a ventricle's upper limit ofvulnerability, and therefore the therapeutic shock is delivered with asufficiently short interval after the sensed QRS complex to precede theinner limit of vulnerability at the therapeutic shock strength.Therefore, the prepulse is synchronized at QRS complex onset (Hou et al,Determination of ventricular vulnerable period and ventricularfibrillation threshold by use of T-wave shocks in patients undergoingimplantation of cardioverter—defibrillators, Circulation 1995; 92:2558-2564). In patients with right-ventricular conduction delays,synchronization to a far-field electrogram may be required because thebipolar right-ventricular electrogram occurs late in the QRS complex.

The prepulse may be an electrical, auditory, or vibro-tactile stimulus.ICD 30 may deliver the prepulse over the same electrode system used todeliver the therapeutic shock or over a different pathway. Prepulses mayinclude the following: (1) electrical pulses delivered between twocardiac (endocardial, epicardial, or extrapericardial) electrodes orbetween one intracardiac electrode and an extracardiac electrode, forexample right atrial/superior vena cava electrode 40, housing electrode46, or a subcutaneous electrode (not illustrated); (2) electrical pulsesdelivered between two extra cardiac electrodes including any combinationof the housing 46, small electrodes suspended from and electricallycoupled to ICD 30, an additional electrode in the ICD pocket or anadjacent pocket, or an electrode implanted at a distance from thepocket; (3) acoustic pulses delivered from a speaker in ICD 30; or (4)vibro-tactile stimuli delivered to muscle, bone, or nerve via ICD 30 orfrom a remote stimulator controlled by the pulse generator. In the lastcase, communication between the pulse generator and ICD 30 may bedescribed by standard wire or wireless methods in a same manner astelemetry communications.

If an electrical prepulse is used, the range of prepulse stimulusstrengths vary from 5 V to 1000 V and the duration of prepulse stimulifrom 0.1 ms to 25 ms. The preferred strengths are in the range of 10 Vto 100 V with preferred durations from 1 ms to 10 ms. Auditory stimulivary in intensity from 0.1 dB(A) to 100 dB(A) above ambient noise andfrom 0.1 ms to 100 ms in duration. The preferred strengths range from 5dB(A) to 15 dB(A) above ambient noise with durations from 15 ms to 25ms.

Optimal prepulse characteristics are determined on a patient-specificbasis or are preset with default parameters. The method for programminga patient specific prepulse intensity and interval is as follows: Theinitial prepulse interval is set near the median optimal interval forthe population (about 100 ms), and the initial intensity is set slightlybelow the median sensory threshold. The prepulse is then deliveredsynchronously with a QRS complex. If it is below the patient's sensorythreshold, the stimulus strength is incremented, and the process isiterated until the patient identifies the prepulse reliably. Theprepulse intensity is further increased in small increments until thepatient judges the prepulse to be slightly uncomfortable. It is thenprogrammed to a level slightly below this discomfort level.

The descriptions above and the accompanying drawings should beinterpreted in the illustrative and not the limited sense. While theinvention has been disclosed in connection with the preferred embodimentor embodiments thereof, it should be understood that there may be otherembodiments which fall within the scope of the invention as defined bythe following claims. Where a claim, if any, is expressed as a means orstep for performing a specified function it is intended that such claimbe construed to cover the corresponding structure, material, or actsdescribed in the specification and equivalents thereof, including bothstructural equivalents and equivalent structures, material-basedequivalents and equivalent materials, and act-based equivalents andequivalent acts.

The invention claimed is:
 1. An apparatus for cardioverting ordefibrillating a patient's heart, comprising: a set of cardioversionelectrodes applicable to the patient's body; means for applying apatient-perceptible stimulus to a portion of the patient's body otherthan the patient's heart other than by means of the set of cardioversionelectrodes; and means for delivering a high voltage shock to thepatient's heart by means of electrodes within the set of cardioversionelectrodes within 20 to 500 milliseconds following initiation of thepatient perceptible stimulus.
 2. The apparatus of claim 1 wherein themeans for applying the patient-perceptible stimulus comprises means forapplying electrical stimulation.
 3. The apparatus of claim 2 wherein themeans for applying electrical stimulation comprises means for applyingelectrical stimulation of at least 10 volts.
 4. The apparatus of claim 3wherein the means for applying electrical stimulation comprises meansfor applying electrical stimulation of less than 1000 volts.
 5. Theapparatus of claim 3 wherein the means for applying electricalstimulation comprises the means for applying electrical stimulation ofless than 100 volts.
 6. The apparatus of claim 3 wherein the means forapplying electrical stimulation comprises means for applying electricalstimulation for a period of 0.05 to 25 milliseconds.
 7. The apparatus ofclaim 1 wherein the means for applying the patient-perceptible stimuluscomprises means for delivering auditory stimulation.
 8. The apparatus ofclaim 7, wherein the means for delivering auditory stimulation comprisesmeans for delivering auditory stimulation at an intensity from 0.1 dB(A)to 100 dB(A) above an existing ambient noise level.
 9. The apparatus ofclaim 8, wherein the means for delivering auditory stimulation comprisesmeans for delivering auditory stimulation at an intensity from 5 dB(A)to 15 dB(A) above said existing ambient noise level.
 10. The apparatusof claim 1 wherein the means for applying the patient-perceptiblestimulus comprises means for delivering tactile stimulation.
 11. Theapparatus of claim 1 wherein the means for applying thepatient-perceptible stimulus comprises means for applying stimulation toa body part selected from the group of the patient's body partscomprising the patient's ear, skeletal muscle, bone, or nerve.
 12. Anapparatus for delivering a painful treatment to a portion of a patient'sbody comprising: applying means for delivery of the painful therapy to afirst portion of the patient's body; means for applying apatient-perceptible stimulus to a second, portion of the patient's bodyother than the first portion employing means other than the means fordelivery of the painful therapy; and means for delivering the painfultherapy within 20 to 500 milliseconds following initiation of thepatient-perceptible stimulus.
 13. The apparatus of claim 12 wherein themeans for applying a patient-perceptible stimulus comprises means forapplying electrical stimulation.
 14. The apparatus of claim 13 whereinthe means for applying electrical stimulation comprises means forapplying electrical stimulation of at least 10 volts.
 15. The apparatusof claim 13 wherein the means for applying electrical stimulationcomprises means for applying electrical stimulation of less than 1000volts.
 16. The apparatus of claim 15 wherein the means for applyingelectrical stimulation comprises means for applying electricalstimulation of less than 100 volts.
 17. The apparatus of claim 13wherein the means for applying electrical stimulation comprises meansfor applying electrical stimulation for a period of 0.05 to 25milliseconds.
 18. The apparatus of claim 12 wherein the means forapplying a patient-perceptible stimulus comprises means for deliveringauditory stimulation.
 19. The apparatus of claim 18, wherein the meansfor delivering auditory stimulation comprises means for deliveringauditory stimulation at an intensity from 0.1 dB(A) to 100 dB(A) abovean existing ambient noise level.
 20. The apparatus of claim 19, whereinthe means for delivering auditory stimulation comprises means fordelivering auditory stimulation at an intensity from 5 dB(A) to 15 dB(A)above said existing ambient noise level.
 21. The apparatus of claim 12wherein the means for applying a patient-perceptible stimulus comprisesmeans for applying tactile stimulation.
 22. The apparatus of claim 12wherein the means for applying a patient-perceptible stimulus comprisesmeans for applying stimulation to a body part selected from the group ofthe patient's body parts comprising the patient's ear, skeletal muscle,bone, or nerve.
 23. The apparatus of claim 1 or claim 12 wherein themeans for delivering the painful therapy comprises means for deliveringa cardioversion or defibrillation pulse.